%0 Journal Article %1 Wojnowski.2005 %A Wojnowski, Leszek %A Kulle, Bettina %A Schirmer, Markus %A Schlüter, Gregor %A Schmidt, Albrecht %A Rosenberger, Albert %A Vonhof, Stefan %A Bickeböller, Heike %A Toliat, Mohammad Reza %A Suk, Eun-Kyung %A Tzvetkov, Mladen %A Kruger, Anke %A Seifert, Silvia %A Kloess, Marita %A Hahn, Heidi %A Loeffler, Markus %A Nürnberg, Peter %A Pfreundschuh, Michael %A Trümper, Lorenz %A Brockmöller, Jürgen %A Hasenfuss, Gerd %D 2005 %J Circulation %K IMISE-Publikationen %N 24 %P 3754–3762 %T NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity %V 112 %X BACKGROUND A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity ACT), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT. METHODS AND RESULTS We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2\%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, -212A-->G; symbols with right-pointing arrows, as edited?' odds ratio OR, 2.5; 95\% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95\% CI, 1.0 to 3.9) and with the variant 7508T-->A (rs13058338; OR, 2.6; 95\% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95\% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95\% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT. CONCLUSIONS Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.

@article{Wojnowski.2005, abstract = {BACKGROUND A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT. METHODS AND RESULTS We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2\%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, -212A-->G; symbols with right-pointing arrows, as edited?' odds ratio [OR], 2.5; 95\% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95\% CI, 1.0 to 3.9) and with the variant 7508T-->A (rs13058338; OR, 2.6; 95\% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95\% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95\% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT. CONCLUSIONS Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT.}, added-at = {2014-10-15T15:04:33.000+0200}, author = {Wojnowski, Leszek and Kulle, Bettina and Schirmer, Markus and Schlüter, Gregor and Schmidt, Albrecht and Rosenberger, Albert and Vonhof, Stefan and Bickeböller, Heike and Toliat, Mohammad Reza and Suk, Eun-Kyung and Tzvetkov, Mladen and Kruger, Anke and Seifert, Silvia and Kloess, Marita and Hahn, Heidi and Loeffler, Markus and Nürnberg, Peter and Pfreundschuh, Michael and Trümper, Lorenz and Brockmöller, Jürgen and Hasenfuss, Gerd}, biburl = {https://www.bibsonomy.org/bibtex/26f0e943e23eb589d63245fdb60e79df5/drtester}, interhash = {8d525952052f4539d303e6dd9ea7fa58}, intrahash = {6f0e943e23eb589d63245fdb60e79df5}, journal = {Circulation}, keywords = {IMISE-Publikationen}, number = 24, pages = {3754–3762}, timestamp = {2014-12-03T00:09:23.000+0100}, title = {NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity}, volume = 112, year = 2005 }